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Progressive muscle relaxation (PMR) is an under-utilized Level A evidence-based treatment for migraine prevention. We studied the feasibility and acceptability of smartphone application (app)-based PMR for migraine in a neurology setting, explored whether app-based PMR might reduce headache (HA) days, and examined potential predictors of app and/or PMR use. In this single-arm pilot study, adults with ICHD3 migraine, 4+ HA days/month, a smartphone, and no prior behavioral migraine therapy in the past year were asked to complete a daily HA diary and do PMR for 20 min/day for 90 days. Outcomes were: adherence to PMR (no. and duration of audio plays) and frequency of diary use. Predictors in the models were baseline demographics, HA-specific variables, baseline PROMIS (patient-reported outcomes measurement information system) depression and anxiety scores, presence of overlapping pain conditions studied and app satisfaction scores at time of enrollment. Fifty-one patients enrolled (94% female). Mean age was 39 ± 13 years. The majority (63%) had severe migraine disability at baseline (MIDAS). PMR was played 22 ± 21 days on average. Mean/session duration was 11 ± 7 min. About half (47%) of uses were 1+ time/week and 35% of uses were 2+ times/week. There was a decline in use/week. On average, high users (PMR 2+ days/week in the first month) had 4 fewer days of reported HAs in month 2 vs. month 1, whereas low PMR users (PMR < 2 days/week in the first month) had only 2 fewer HA days in month 2. PROMIS depression score was negatively associated with the log odds of using the diary at least once (vs. no activity) in a week (OR = 0.70, 95% CI = [0.55, 0.85]) and of doing the PMR at least once in a week (OR = 0.77, 95% CI = [0.68, 0.91]). PROMIS anxiety was positively associated with using the diary at least once every week (OR = 1.33, 95% CI = [1.09, 1.73]) and with doing the PMR at least once every week (OR = 1.14 [95% CI = [1.02, 1.31]). In conclusion, about half of participants used smartphone-based PMR intervention based upon a brief, initial introduction to the app. App use was associated with reduction in HA days. Higher depression scores were negatively associated with diary and PMR use, whereas higher anxiety scores were positively associated.
Learn More >Measuring patients' experiences of health services has become an essential part of quality of care reporting and a means for identifying opportunities for improvement. This study aimed to evaluate change in patient experience in an interdisciplinary primary care program and to estimate the impact on patient experience of sociodemographic, function, pain and general health status, resource utilization, and process variables.
Learn More >Peripheral and central neurons in the pain pathway are well equipped to detect and respond to extracellular stimuli such as pro-inflammatory mediators and neurotransmitters through the cell surface expression of receptors that can mediate rapid intracellular signaling. Following injury or infection, activation of cell surface G protein-coupled receptors (GPCRs) initiates cell signaling processes that lead to the generation of action potentials in neurons or inflammatory responses such as cytokine secretion by immune cells. However, it is now appreciated that cell surface events alone may not be sufficient for all receptors to generate their complete signaling repertoire. Following an initial wave of signaling at the cell surface, active GPCRs can engage with endocytic proteins such as the adaptor protein β-arrestin (βArr) to promote clathrin-mediated internalization. Classically, βArr-mediated internalization of GPCRs was hypothesized to terminate signaling, yet for multiple GPCRs known to contribute to pain, it has been demonstrated that endocytosis can also promote a unique "second wave" of signaling from intracellular membranes, including those of endosomes and the Golgi, that is spatiotemporally distinct from initial cell-surface events. In the context of pain, understanding the cellular and molecular mechanisms that drive spatiotemporal signaling of GPCRs is invaluable for understanding how pain occurs and persists, and how current analgesics achieve efficacy or promote side-effects. This review article discusses the importance of receptor localization for signaling outcomes of pro- and anti-nociceptive GPCRs, and new analgesic opportunities emerging through the development of "location-biased" ligands that favor binding with intracellular GPCR populations.
Learn More >ATP-sensitive potassium (K) channels are found in the nervous system and are downstream targets of opioid receptors. K channel activity can effect morphine efficacy and may beneficial for relieving chronic pain in the peripheral and central nervous system. Unfortunately, the K channels exists as a heterooctomers, and the exact subtypes responsible for the contribution to chronic pain and opioid signaling in either dorsal root ganglia (DRG) or the spinal cord are yet unknown. Chronic opioid exposure (15 mg/kg morphine, s.c., twice daily) over 5 days produces significant downregulation of Kir6.2 and SUR1 in the spinal cord and DRG of mice. studies also conclude potassium flux after K channel agonist stimulation is decreased in neuroblastoma cells treated with morphine for several days. Mice lacking the K channel SUR1 subunit have reduced opioid efficacy in mechanical paw withdrawal behavioral responses compared to wild-type and heterozygous littermates (5 and 15 mg/kg, s.c., morphine). Using either short hairpin RNA (shRNA) or SUR1 cre-lox strategies, downregulation of SUR1 subtype K channels in the spinal cord and DRG of mice potentiated the development of morphine tolerance and withdrawal. Opioid tolerance was attenuated with intraplantar injection of SUR1 agonists, such as diazoxide and NN-414 (100 μM, 10 μL) compared to vehicle treated animals. These studies are an important first step in determining the role of K channel subunits in antinociception, opioid signaling, and the development of opioid tolerance, and shed light on the potential translational ability of K channel targeting pharmaceuticals and their possible future clinical utilization. These data suggest that increasing neuronal K channel activity in the peripheral nervous system may be a viable option to alleviate opioid tolerance and withdrawal.
Learn More >Diabetic neuropathy is a serious complication for diabetic patients involving the nervous system. This disease is a quiet but painful condition caused by chronically high blood glucose levels. It is reported that high mobility group box 1 protein (HMGB1) participates in the development of neuropathic pain. This study aimed to explore the role of microRNA (miR)-193a in diabetic neuropathic pain through the regulation of HMGB1.
Learn More >Depression is one of the most common comorbidities in patients with chronic low back pain. However, the mechanisms of depression in chronic low back pain patients and the effect of antidepressants on the comorbidity of pain and depression need to be further explored. The establishment of the appropriate animal models and of more effective therapies is critical for this comorbidity. Lumbar disc herniation (LDH) is the most common disease that causes low back pain. The current study examined whether an LDH model shows behavioral and biochemical alterations that are in accordance with the characteristics of the comorbidity of pain and depression and tested the effect of fluoxetine (FLX) on these measures. The current study examined whether an LDH model showed the behavioral and biochemical alterations that were in accordance with the characteristics of the comorbidity of pain and depression and tested the effect of FLX on these measures. The LDH animal model was generated by the implantation of the autologous nucleus pulposus on the left L5 nerve root just proximal to the dorsal root ganglion in Wistar rats. Pain intensity was evaluated by mechanical allodynia and thermal hyperalgesia, and changes in depressive behavior were examined by the taste preference and forced swim tests. Hippocampal serotonin (5-HT) levels were measured by liquid chromatography-mass spectrometry, and tumor necrosis factor-α (TNF-α) mRNA was quantified using real-time reverse transcriptase PCR. LDH resulted in chronic pain, which further induced depressive behavior that persisted for 6 weeks after surgery. There were decreased 5-HT concentrations and upregulated TNF-α mRNA levels that were accompanied by behavioral changes. FLX treatment improved depressive behavior and moderately alleviated pain through increased 5-HT concentrations, and inhibited TNF-α mRNA expression. In summary, our studies provide initial evidence that the LDH chronic pain model might serve as a model of the comorbidity of low back pain and depression. The finding that FLX improved depressive behavior and pain through normalized 5-HT concentrations and TNF-α mRNA expression establishes the initial mechanism of the comorbidity of pain and depression.
Learn More >Chronic pain disproportionately affects older adults, severely impacting quality of life and independent living, with musculoskeletal pain most prevalent. Chronic musculoskeletal pain is associated with specific structural alterations in the brain and interindividual variability in brain structure is likely an important contributor to susceptibility for the development of chronic pain. However, understanding of age-related structural changes in the brain and their associations with chronic musculoskeletal pain is currently limited. Oxytocin (OT), a neuropeptide present in the periphery and central nervous system, has been implicated in pain attenuation. Variation of the endogenous OT system (e.g., OT receptor genotype, blood, saliva, and cerebrospinal fluid OT levels) is associated with morphology in brain regions involved in pain processing and modulation. Intranasal OT administration has been shown to attenuate pain. Yet, studies investigating the efficacy of OT for management of chronic musculoskeletal pain are lacking, including among older individuals who are particularly susceptible to the development of chronic musculoskeletal pain. The goal of this focused narrative review was to synthesize previously parallel lines of work on the relationships between chronic pain, brain morphology, and OT in the context of aging. Based on the existing evidence, we propose that research on the use of intranasal OT administration as an intervention for chronic pain in older adults is needed and constitutes a promising future direction for this field. The paper concludes with suggestions for future research in the emerging field, guided by our proposed
Learn More >Migraine is a debilitating primary headache disorder with a poorly understood aetiology. An extensive body of literature supports the theory of migraine as a systemic vascular inflammatory disorder characterised by endothelial dysfunction. It is also well-known that chronic inflammation results in an excessive burden of oxidative stress and therefore cellular dysfunction. In this study the effects of excessive oxidative stress through the phases of female migraine-with-aura (FMA) were evaluated by examining the health of the systems of haemostasis. Blood was obtained from 11 FMA patients at baseline and during the headache phase of migraine, as well as from 8 healthy age-matched female controls. Samples were analysed using thromboelastography (TEG) to evaluate viscoelastic profiles, light microscopy for erythrocyte morphology, Scanning Electron Microscopy (SEM) for erythrocyte and fibrin clot structure, confocal microscopy for β-amyloid detection in fibrin clots. Viscoelastic profiles from platelet poor plasma showed decreased clot reaction times in FMA at baseline (95% CI [5.56, 8.41]) vs. control (95% CI [7.22, 11.68]); as well as decreased time to maximum thrombus generation for the same comparison (95% CI [6.78, 10.20] vs. [8.90, 12.96]). Morphological analysis of erythrocytes indicated widespread macrocytosis, poikilocytosis and eryptosis in the migraineurs. Analysis of fibrin networks indicated that this hypercoagulability may be a result of aberrant fibrin polymerisation kinetics caused by the adoption of a β-amyloid conformation of fibrin(ogen). The results reaffirm the hypercoagulable state in migraine, and would suggest that this state is most likely a result of a systemic inflammatory state which induces oxidative damage to both erythrocytes and fibrin(ogen) in female episodic migraine-with-aura. Furthermore, if the amylodogenic changes to fibrin(ogen) were observed in a larger cohort, this would support theories of micro-embolisation in migraine-with-aura.
Learn More >Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women vs. men. Large transcriptomic resources are now available and can be used to mine for sex differences to gather insight from molecular profiles using donor cohorts. We performed in-depth analysis of 248 human tibial nerve (hTN) transcriptomes from the GTEx Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential gene expression. Many of the more abundant genes in men are associated with inflammation and appear to be primarily expressed by glia or immune cells, with some genes downstream of Notch signaling. In women, we find the differentially expressed transcription factor SP4 that is known to drive a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 differentially expressed (DE) genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTEx database, we identify a subset of DE, sexually dimorphic genes in diseases associated with chronic pain: arthritis and Type II diabetes. Our work creates a unique resource that identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.
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